Glaucoma is an ophthalmic disease that leads to irreversible visual impairment. It is the fourth most common cause of blindness and the second most common cause of visual loss in the United States, and the most common cause of irreversible visual loss among African-Americans. Generally speaking, the disease is characterized by a progressive neuropathy caused at least in part by deleterious effects resulting from increased intraocular pressure on the optic nerve. Open-angle glaucoma constitutes approximately 90% of all primary glaucoma and is characterized by abnormally high resistance to fluid (aqueous humor) drainage from the eye. Normal resistance is required to maintain an intraocular pressure sufficient to maintain the shape of the eye for optical integrity. This resistance is provided by the trabecular meshwork, a complex tissue consisting of specialized endothelial cells, connective tissue beams and extracellular matrix. The resistance of the trabecular meshwork normally is such that intraocular pressure is ˜16 mm Hg, a pressure at which aqueous humor leaves the eye at the same rate at which it is produced (2.5 μL/minute). Extremely high pressures (e.g., 70 mm Hg.) may cause blindness within only a few days. See P. L. Kaufman and T. W. Mittag, “Medical Therapy Of Glaucoma,” Ch. 9, Sec. II (pp. 9.7-9.30), in P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); A. C. Guyton, Textbook of Medical Physiology (W. B. Saunders Co., Sixth Ed.), pp. 386-89 (1981).
Currently, the treatment of glaucoma and controlling of elevated intraocular pressure is approached using a variety of therapeutic agents across a wide spectrum of chemical classes.
The drug classes most frequently employed to reduce intraocular pressure rely on suppression of aqueous humor formation (e.g., beta-blockers, α2 adrenergic agonists, carbonic anhydrase inhibitors) or enhancement of uveoscleral outflow (prostaglandin analogues). There are no current anti-glaucoma drugs in common use that act directly on the trabecular meshwork. Pilocarpine reduces flow resistance through the trabecular meshwork secondarily, based on meshwork deformation consequent to drug-induced ciliary muscle contraction, but its use is limited by the need for 3-4 times daily administration and local side effects, especially miosis. Epinephrine apparently acts directly on the meshwork cells to increase facility via a β2 adrenergic receptor-mediated pathway, but is seldom used clinically because of receptor-mediated local and systemic side effects, a high frequency of local allergy, and only modest efficacy and inter-patient variability in responsiveness.
Trabeculectomy is the most common form of glaucoma filtration surgery and remains as the first-line therapy for surgical reduction of pharmacologically uncontrolled intraocular pressure in primary open angle glaucoma. This procedure establishes a limbal fistula through which aqueous humor drains into the subconjunctival space establishing a filtering bleb to lower intraocular pressure. The success of the procedure is highly dependent on pharmacological modulation of wound healing.
A major advance in the surgical management of glaucoma has been the use of antimetabolites to prevent scarring after glaucoma filtration surgery. Postoperative scarring of the filtering bleb is the most crucial factor in determining the short and long-term outcome of modern glaucoma filtration surgery. Antimetabolites mitomycin C (MMC) and 5-fluorouracil (5-FU) are the most widely used agents to suppress scarring and the failure of the filtering bleb. In a large retrospective study, conventionally performed trabeculectomy has shown a failure rate of up to 30% within 3 months after surgery. To lower the incidence of this detrimental complication, various methods have been investigated in order to avoid the naturally occurring scarring of the filtering bleb, mostly dealing with the intraoperative or postoperative application of antimetabolic drugs—that is, 5-fluorouracil (5-FU) or mitomycin C (MMC), the two most widely used cytotoxic agents.
Despite their positive long-term effect on prolonged filtration, the application of cytotoxic drugs to a surgically opened eye increases the incidence of severe complications such as concomitant increases in vision threatening complications. MMC and 5-FU exhibit a high incidence of severe post-application complications; their side effects mainly affect the corneal epithelium and their clinical uses are limited by severe pain and discomfort to the patient. No sufficient method has been established to achieve satisfying postoperative long term surgical results with only minimal or no side effects for the patient.
U.S. Pat. Nos. 6,586,425; 6,110,912; and 5,798,380 disclose a method for the treatment of glaucoma using compounds that affect the actin filament integrity of the eye to enhance aqueous humor outflow. These patents also specifically disclose kinase inhibitors and latrunculin-A, latrunculin-B, swinholide-A, and jasplakinolide, which cause a perturbation of the actin cytoskeleton in the trabecular meshwork or the modulation of its interactions with the underlying membrane. Perturbation of the cytoskeleton and the associated adhesions reduces the resistance of the trabecular meshwork to fluid flow and thereby reduces intraocular pressure.
Latrunculins are soluble in dimethyl sulfoxide (DMSO), but they have a very low aqueous solubility, due to the largely lipophilic nature of the latrunculins that are large macrocylic compounds. DMSO is not permissible in an ophthalmic formulation for human use. Latrunculin-B is typically dissolved in DMSO as a stock solution, and stored at −20° C. for long-term stability (Okka, et. al., Trans. Am. Ophthalmol. Soc. 102: 251-259 (2004)). Known liquid latrunculin formulations are not acceptable pharmaceutical formulations because of one or more of the following problems: unwanted side affects such as toxicity due to vehicle or adjuvant, low solubility of the latrunculin without the use of DMSO, and poor stability due to latrunculin degradation over time.
There exists a need for a pharmaceutical formulation that can be used to treat glaucoma, to modulate wound healing after trabeculectomy, and to treat other diseases or disorders that are affected by the integrity of the actin cytoskeleton.